This application is a proposal for a renewal of our program project, Healthy Aging and Senile Dementia (HASD). The program project began as an expansion of longitudinal studies of subjects with mild senile dementia of the Alzheimer type (SDAT) and matched healthy control subjects. In this renewal there is a continued focus on the behavioral and biomedical correlates of the clinical course of defined groups of SDAT subjects in comparison with the course of healthy aging in control subjects, Five interactive and supportive Cores are proposed: Clinical, Psychometric, Neuropathology, Biostatistics and Administration. Three of our current projects are to continue. Project 1 will continue to study demented and nondemented subjects aged 80 and over with respect to their longitudinal clinical and psychometric performance during life, neuropathologic data postmortem, and their interrelationships. The aim is to develop and help validate guidelines for separating Alzheimer's disease (AD) from nonAD in the very old. In Project 2 there will continue a study of the distribution and density of plaques, tangles and related immunohistochemical markers in the ventral forebrain of carefully assessed demented and nondemented old individuals. The goal is to define the pattern of pathologic changes in the earliest stage of AD by concentrating on very old nondemented subjects. Project 3 will build on current results that suggest very mild and mild SDAT subjects exhibit breakdown in the inhibitory control of irrelevant representation during memory processing. Utilizing basic healthy aging and mild SDAT. Based on preliminary results that indicate normal elderly and very mild SDAT subjects show improved memory with optimal elevations (different for each group) of plasma glucose, Project 4 will study the effect of hyperglycemia on memory performance and glucoregulatory hormone levels in those subjects groups in longitudinal experiments. Simultaneously, the effects of increased insulin levels on memory performance will also be assessed.